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Disubstituted bis-THF moieties as new P2 ligands in nonpeptidal HIV-1 protease inhibitors

by Konrad Hohlfeld, Cyrille Tomassi, Jörg Kurt Wegner, Bart Kesteleyn, Bruno Linclau
ACS Medicinal Chemistry Letters ()


HIV-1 protease inhibitors (PIs) remain a powerful tool in the battle against HIV. The recently approved nonpeptidal HIV-protease inhibitor darunavir has been reported to be highly active against the wild-type virus as well as against a series of mutant strains. A rigid bis-tetrahydrofuran (bis-THF) moiety, with its two well-positioned hydrogen bond acceptors, has proven to play a crucial role in the interaction of darunavir with the enzyme. Based on the darunavir structure, a series of novel disubstituted bis-THF containing HIV-1 protease inhibitors have been developed, which show very good activities against wild-type HIV-1 protease as well as a panel of multi-PI resistant mutant strains. In particular, PIs have been synthesised that show equivalent and greater activity for mutant strains compared to wild-type HIV-1 protease. The new ligands are derived from a selectively protected bis-THF diol scaffold, the synthesis of which has been developed in our group. Alongside the synthesis, a design rational, as well as results from biological testing and molecular modelling will be described

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